In the treatment of Diabetes mellitus many varieties of insulin preparations have been suggested to the art. Some of these preparations are rapid-acting and others have a more or less prolonged action.
Rapid acting insulin preparations may be used in acute situations, such as hyperglycemic coma, during surgery, during pregnancy, and in severe infections. Furthermore, multiple, daily injections of rapid-acting insulin preparations may improve control in diabetics who have proved difficult to control with longer-acting insulin.
In the recent years there has been an increasing interest in an insulin treatment which approaches the insulin secretion from the beta-cells of the healthy organism, i.e. supply of insulin in connection with meals and maintenance of a basal insulin level. Clinical investigations have shown that diabetics can obtain nearly normal insulin and glucose concentrations by means of one daily injection of insulin with prolonged action to cover the basal need, supplemented with injections of smaller amounts (bolus) of rapid-acting insulin before the main meals.
Rapid-acting insulins are also used in mixtures with intermediate and long-acting insulins for treatment of diabetics requiring a stronger initial effect in addition to the delayed action of intermediate and long-acting insulins.
Finally, rapid-acting insulin is used in continuous insulin delivery systems.
By subcutaneous injection of rapid-acting insulin solutions an initial delay in absorption has been observed (Binder, Diabetes Care 7, No. 2 (1984), 188-199). A delay in absorption resulting in a slower onset of action is however undesirable when a strict metabolic control is aimed at. Mixing of rapid-acting insulin solutions with longer-acting insulin preparations may furthermore result in reduced rate of absorption of the rapid-acting insulin.
Accordingly, there is a need for rapid-acting insulin solutions with a faster onset of action upon subcutaneous injection and an improved miscibility with protracted insulin preparations.
A further drawback of known rapid-acting insulin solution is the tendency of insulin to fibrillate and precipitate out in the insulin solutions used for continuous insulin delivery thereby obstructing mechanical parts and delivery catheters.
Finally there is a need for alternative insulin preparations for the treatment of patients resistent to normal insulin.
It is the object of the present invention to provide novel rapid-acting insulin solutions with one or more of the following improved properties:
1) faster onset of action by subcutaneous injection or other routes of administration PA1 2) improved miscibility with protracted insulin preparations PA1 3) reduced tendency to fibrillation when used in implantable delivery systems, and PA1 4) usable for the treatment of resistent patients (low affinity for preexisting antibodies).
The objectives of this invention are achieved with injectable aqueous solutions of the novel human insulin analogues hereinafter described.
A large number of insulin analogues have been described in the past. M arki et al. (Hoppe-Seyler's Z. Physiol.Chem., 360 (1979), 1619-1632) describe synthesis of analogues of human insulin that differ from human insulin in the replacement of a single amino acid in positions 2, 5, 6, 7, 8, and 11 of the A-chain and 5, 7, 13, and 16 of the B-chain affording new insights into the intriguing structure-activity relationship of insulin. Further studies modified the major receptor binding area in insulin (B(22)-B(26)) to investigate the impact of such mutation on the receptor binding activity. The known human insulin analogues will, however, not exhibit the properties desired by the inventors hereof.
It is known that sulphated insulins have a substantially lower tendency to fibrillation (Albisser et al., Desired Characteristics of insulin to be used in infusion pumps. In: Gueriguian J.L. et al., eds. US Pharmacopeial Convention, Rockwille, Md., pp. 84-95) and exhibit a low antigenicity. Sulphated insulins are, however, a heterogeneous mixture of at least nine different insulin derivatives containing on average 4.5 sulphate ester groups per molecule. Sulphated insulins have furthermore a reduced insulin activity, being about 20% of the activity of native insulin. A further drawback of sulphated insulins as compared to native insulin is that they needlessly contain amino acid residues which are chemically modified, i.e. amino acids which do not occur naturally.
It is therefore a further object of the present invention to provide insulin analogues which are homogeneous, have a higher biological activity than sulphated insulins and which furthermore preferably only contain naturally occuring amino acids.
By "insulin analogues" as used herein is meant a compound having a molecular structure similar to that of human insulin including the disulphide bridges between A(7)Cys and B(7)Cys and between A(20)Cys and B(19)Cys and an internal disulphide bridge between A(6)Cys and A(11)Cys and with insulin activity.